Process for preparing oxymorphone, naltrexone, and buprenorphine

ABSTRACT

Methods are provided which include converting oripavine to other opiates, including converting oripavine to naltrexone, buprenorphine, 14-hydroxymorphinone and/or converting 14-hydroxymorphinone to oxymorphone. Purification and salt formation are optionally included.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.12/446,172, which is a National Phase Application of InternationalApplication PCT/US2007/081513, filed Oct. 16, 2007, which claimspriority to U.S. Provisional Application No. 60/829,817, filed Oct. 17,2006, and to U.S. Provisional Application No. 61/007,897, filed Dec. 14,2006, for which a Request to Convert Non-Provisional Application toProvisional Application Under 37 C.F.R. §1.53(c)(2) was filed Oct. 11,2007, from U.S. application Ser. No. 11/611,049, filed Dec. 14, 2006,the disclosures of each of which is incorporated herein by reference inits entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to preparation of opiates such as14-hydroxymorphinone, oxymorphone, naltrexone, methylnaltrexone,buprenorphine, nalmefene, nalorphine, and naloxone from oripavine.

2. Background of the Invention and Related Art

Oxymorphone, a potent opiate analgesic, is a semi-synthetic substitutefor morphine. It is about ten times as potent as morphine. In the UnitedStates, FDA has approved oxymorphone hydrochloride in oral, parenteraland suppository forms. Naltrexone, methylnaltrexone, buprenorphine,nalmefene, nalorphine, and naloxone are other useful opiates.

Oxymorphone can also be converted to those and other useful compounds,such as nal-compounds, including naloxone.

Oxymorphone is typically synthesized using thebaine, morphine or anothercompound as a starting material. Thebaine, when used, is generallyobtained from the concentrated poppy straw (CSP-T), a poppy extractrelatively rich in thebaine. Reaction schemes for producing oxymorphonefrom thebaine take several steps, to intermediates such as oxycodone,then conversion of the 3-methoxy group of oxycodone to the 3-hydroxygroup of oxymorphone. U.S. Pat. No. 6,291,675, for example, discloses amethod for O-demethylation of the 3-methoxy group of opiates by use of alithium hydride compound, providing a yield of O-demethylated opioid ofat least 23%. U.S. Pat. No. 5,922,876 discloses preparation ofoxymorphone from morphine. The process includes protection of the3-hydroxy group of morphine with an aceto or benzyl group.

Naltrexone is a narcotic antagonist; it also has been used to treatopioid abuse and alcoholic abuse. It can be prepared from thebaine (U.S.Pat. No. 3,332,950) or morphine (U.S. Pat. No. 6,013,796). Buprenorphineis a narcotic agonist/antagonist; it has been used for the treatment ofopioid abuse. It can be prepared from thebaine (U.S. Pat. No.3,433,791).

Features and advantages of the present invention will be set forth inthe description of invention that follows, and will be apparent, inpart, from the description or may be learned by practice of theinvention. The invention will be realized and attained by thecompositions, products, and methods particularly pointed out in thewritten description and claims hereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Unless otherwise stated, a reference to a compound or component includesthe compound or component by itself, as well as in combination withother compounds or components, such as mixtures of compounds.

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly dictates otherwise.

Except where otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained by the present invention. Atthe very least, and not to be considered as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding conventions.

Additionally, the recitation of numerical ranges within thisspecification is considered to be a disclosure of all numerical valuesand ranges within that range. For example, if a range is from about 1 toabout 50, it is deemed to include, for example, 1, 7, 34, 46.1, 23.7, orany other value or range within the range.

Unless otherwise noted, all reactions are run under inert conditions,such as under nitrogen or argon for safety and/or to avoid the formationof N-oxide by-products.

The present inventor has discovered that oripavine can be economicallyconverted to other opiates, such as oxymorphone, naltrexone, andbuprenorphine and derivatives thereof. Any starting material comprisingoripavine may be used. The starting material preferably comprisesgreater than about 50% by weight oripavine, preferably greater thanabout 70%, more preferably greater than about 95%. The starting materialis preferably purified oripavine, or a concentrate of poppy strawcomprising oripavine as the main alkaloid (hereinafter, “CPS-O”).

Preferably, the oripavine comprises “natural oripavine,” but cancomprise oripavine from any source. By “natural oripavine” is meantoripavine obtained from a natural source (e.g., botanical, bioengineeredbacterial, etc.), and is meant to distinguish from oripavine obtained ina laboratory or factory setting by partial or total chemical synthesis,e.g., synthetic or semi-synthetic oripavine. Natural oripavine includes,without limitation, CPS-O, and purified oripavine obtained from CPS-O orother poppy straw.

Preparation of Oxymorphone

Preferably, oripavine is oxidized with an oxidizing agent to obtain14-hydroxymorphinone. The 14-hydroxymorphinone is then preferablyreduced with a reducing agent to obtain oxymorphone. The14-hydroxymorphinone can also be used in other ways, preferably toprepare other products.

The oxidizing agent can comprise any oxidizing agent that permits theconversion of oripavine to 14-hydroxymorphinone, including, but notlimited to, peroxy acids, such as performic acid, peracetic acid, andm-chloroperoxybenzoic acid (MCPBA). Mixtures of oxidizing agents may beused. When a peroxy acid is used, it may be added, or prepared in situ.

When the oxidizing agent comprises a peroxy acid prepared in situ, itmay be prepared in any manner, preferably by combining a peroxide and anacid. Any peroxide or combination of peroxides that can provide a peroxyacid can be used, preferably hydrogen peroxide, for example, aqueoushydrogen peroxide. Any acid or combination of acids that can provide aperoxy acid can be used, preferably formic acid, or acetic acid, forexample, aqueous solutions of formic and/or acetic acid. Performic acidmay be obtained, for example, by combining hydrogen peroxide and formicacid, and peracetic acid may be obtained by combining hydrogen peroxidewith acetic acid.

The reaction may be carried out in any appropriate solvent, preferablyan aqueous solvent. When the oxidizing agent includes a peroxy acid, itis preferred to use a solvent comprising the corresponding acid. Forexample, when the oxidizing agent comprises performic acid, it ispreferred to use a solvent comprising formic acid, and when theoxidizing agent comprises peracetic acid, it is preferred to use asolvent comprising acetic acid. When MCPBA is used, it is preferred touse a solvent comprising acetic acid.

An exemplary process using performic acid as oxidizing agent is:

An exemplary process using MCPBA as oxidizing agent is:

Any temperature that permits the reaction to proceed may be used. Thetemperature need not remain constant, and may vary during the reaction.Higher reaction temperatures speed up the reaction, but may increaseformation of by-products. Different oxidation agents may run optimallyat different temperatures. Reactions employing performic acid, forexample are preferably run in the range of about 20 to 60° C., morepreferably about 40-50° C., even more preferably at about 50° C.Reactions employing MCPBA are preferably run in the range of about 0 to40° C., more preferably about 10-30° C., even more preferably at aboutambient temperature, e.g., about 25° C.

The reaction is run under conditions to convert oripavine to14-hydroxymorphinone. Preferably, at least about 90% of the oripavine isconverted to 14-hydroxymorphinone, more preferably, about 95%, even morepreferably about 98% or 99%. Preferably, the conversion of oripavine to14-hydroxymorphinone will be about 100%.

The remaining amount of oripavine in the reaction mixture, as well asthe amount of 14-hydroxymorphinone produced, can be determined by anymethod, such as by TLC or HPLC.

Any reducing agent may be used to convert 14-hydroxymorphinone tooxymorphone. Catalytic hydrogenation is a preferred method, e.g., with apalladium catalyst, preferably palladium, or palladium hydroxide, onactivated carbon (e.g., Pd/C).

Catalytic hydrogenation may be performed at any suitable pressure, andis preferably done completely, or in part, in a low pressureenvironment. Catalytic hydrogenation preferably includes hydrogenationat or greater than, about 1 atmosphere pressure. By “low pressure” ispreferably meant less than about 10 atm, or less than about 4 atm.Catalytic hydrogenation reactions, therefore, include hydrogenation at,e.g., at about 1-10 or about 1-4 atm. Low pressure hydrogenationgenerally requires less expensive processing and/or lower equipmentcosts than hydrogenation at higher pressures.

The oxidizing and reduction may be performed as a “one pot” process, ormay be done in separate vessels. The 14-hydroxymorphinone may beisolated, but need not be isolated, prior to reduction. In a preferredembodiment, the 14-hydroxymorphinone is not isolated in solid form priorto reduction.

Preferably, the opiate, e.g., oxymorphone, or a salt thereof, ispurified. Preferably, crude oxymorphone is isolated, purified, andconverted to a salt, preferably the hydrochloride salt. An exemplaryprocess for purifying crude oripavine base is:

Purification aids may be used in the purification process. Preferredpurification aids include adsorbents. Some preferred purification aidsinclude activated carbon (commercially available as, e.g., DARCO),and/or powdered cellulose (commercially available as, e.g., SOLKA-FLOC).The reducing agent sodium bisulfite may be used, e.g., when performingthe reaction in the presence of oxidants, e.g., under an oxidizingatmosphere. When the reaction is run under a non-oxidizing atmosphere,e.g., nitrogen gas, it may be possible to omit sodium bisulfite. Otherpurification aids, including purification aids known in the art, may beselected and used by a person of ordinary skill in the art. Purifiedoxymorphone, containing very little 14-hydroxymorphinone, is especiallydesirable because the impurity (14-hydroxymorphinone) is analpha-beta-unsaturated ketone, which may be a carcinogen.

Opiate salts, e.g. of oxymorphone, may also be prepared. Any salt,preferably a therapeutically acceptable salt, may be included in thepresent invention. The hydrochloride is a preferred salt. Methods forpreparing salts of compounds are known in the art. An exemplary processfor preparing the hydrochloride salt of purified oxymorphone is:

Generally, oxymorphone, preferably purified oxymorphone, is suspended ordissolved in a liquid, preferably an alcohol and/or water; and morepreferably ethanol, 2-propanol, combinations thereof, and combinationswith water. Then, an acid, such as hydrochloric acid (preferablyconcentrated or gaseous HCl), is added to the mixture at a highertemperature. After cooling for a period of time, preferably once thereaction is complete or substantially complete, the oxymorphone salt isseparated from the mixture, washed, and dried.

Oxymorphone can also be converted to other compounds, such as naloxone.Methods for effecting this conversion are known in the art.

Preparation of Naltrexone

Oripavine can also be converted to naltrexone. One scheme for performingthis conversion is shown in Scheme 1, below:

Generally, the phenolic hydroxyl group in the 3-position of oripavinecan be protected, for example by a benzyl group (or a substituted benzylgroup, etc.) to 3-benzyl-oripavine, (1-1), followed by N-demethylationwith a demethylation agent such as 1-chloroethyl chloroformate (ACE-Cl),and then reacting with methanol to obtain 3-benzyl-nororipavine, (1-2).The nor-product is alkylated with (chloromethyl)cyclopropane (or otherhalomethylcyclopropane, or tosylmethylcyclopropane, for example) to give3-benzyl-17-cyclopropylmethylnororipavine, (1-3). This is oxidized to3-benzyl-17-cyclopropylmethyl-14-hydroxynororipavine, (1-4), by reactingwith an oxidation agent such as a peroxy acid like peroxyformic acid,peroxyacetic acid, or MCPBA. The product, which may or may not beisolated, can be hydrogenated to reduce the 7,8-double bond and tode-benzylate at the same time to give naltrexone, which can be convertedto a salt.

Preparation of Buprenorphine

Oripavine can also be converted to buprenorphine. One scheme forperforming this conversion is shown in Scheme 2, below:

Generally, oripavine can be reacted with methyl vinyl ketone under DielsAlder conditions to give7α-acetyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine, (2-1), which canbe protected for the 3-phenolic hydroxyl group by, for example, a benzylgroup (or a substituted benzyl group, etc.) to7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine, (2-2).This is de-methylated by reacting with a demethylating agent, such asACE-Cl, and then refluxing in methanol to the nor product7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine,(2-3), which is alkylated with (chloromethyl)-cyclopropane (or otherhalomethylcyclopropane, or tosylmethylcyclopropane, for example) to7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine,(2-4). This is reacted with a Grignard reagent, tert-butyl magnesiumchloride (or tert-butyl lithium), in THF to3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetruhydronororipavine,(2-5), which is reduced and de-benzylated at the same time byhydrogenation with Pd/C or Pd(OH)₂ in hydrogen to buprenorphine, whichcan be converted to a salt.

Alternatively, the hydroxyl group of oripavine is protected with abenzyl group first and then reacted with methyl vinyl ketone under DielsAlder conditions.

Oxymorphone, naltrexone, or buprenorphine, or salts thereof, preferablyHCl salts, may be prepared into pharmaceutical dosage forms.Pharmaceutical dosage forms include, but are not limited to, tablets,pills, capsules (including hard or soft gelatin capsules), parenteralformulations, suppositories, patches, and powders. Generally, a salt,e.g., the hydrochloride, is preferred. Oxymorphone base may be used,e.g., for transdermal patches. Preferred dosage forms include parenteralformulations and suppositories.

Pharmaceutical dosage forms comprising, e.g., oxymorphone, naltrexone,or buprenorphine, may include one or more pharmaceutically acceptableexcipients, and can be selected by those of ordinary skill in the art.Pharmaceutically acceptable excipients include, but are not limited to,carrier vehicles, stabilizing agents, solubilizing agents, lubricatingagents, flow agents, bulking agents, control release agents,disintegrating agents, binding agents, pigments, flavoring agents, andcoating agents.

EXAMPLES Synthesis of Oxymorphone Example 1 Crude Oxymorphone fromOripavine

To a stirred oripavine (166.7 mg; 0.561 mmol) solution in 0.5 mL 30%formic acid (4.185 mmol) was added 0.1 ml 30% hydrogen peroxide (0.979mmol), and the resulting mixture was stirred at 50° C. After completetransformation as indicated by TLC, the reaction mixture was transferredto a Parr Shaker, and 5% Pd/C (51.9 mg) was added. The mixture washydrogenated at room temperature under 28 inch-Hg overnight, filtered,basified with NH₄OH, and extracted with methylene chloride (5×15 ml).The extract was evaporated under reduced pressure to give 113.4 mg of apale yellow solid, yield 67.1%. The product has an identical retentiontime in HPLC and same R_(f) value in TLC to an oxymorphone standard.

Example 2 Crude Oxymorphone from Oripavine

Oripavine (50.0 g, 168 mmol), de-ionized water (70 ml), and 90% formicacid (42.0 g, 0.821 mol) were charged into a 500 ml 3-necked roundbottom flask. The solution was stirred at 30-40° C. and to thecomposition was added 35% hydrogen peroxide, drop-wise (19.7 g, 0.203mol), while keeping the temperature below 40° C. Upon completion of theaddition, the mixture was stirred at 40-50° C. for 4 hours. The reactionmixture was transferred to a 1-L hydrogenation vessel and 5% Pd/C (3.2g) and 2-propanol (160 ml) were added. Hydrogenation proceeded at 46-52psig at room temperature overnight (about 18 h). The catalyst in themixture was filtered off. The filtrate and washings are combined andbasified with 50% NaOH (59.6 g) to pH 9.16. The temperature was kept atbelow 30° C. during the basification. The slurry was stirred at roomtemperature for 1 hour, and filtered to give a brown solid, which wasthen dried at 90° C. and 25″ Hg vacuum overnight to provide the crudeoxymorphone as light brown solids (48.2 g, 160 mmol, 95.2% yield).

Example 2b Crude Oxymorphone from Oripavine

Oripavine (50.0 g, 168 mmol), was converted to 14-hydroxymorphinone asin Example 2 through and including addition of hydrogen peroxide. Uponcompletion of the addition, the mixture was stirred at 40-50° C. ByHPLC, it was determined that the area ratio of14-hydroxymorphinone:oripavine is 27.2:72.8 after 1 hour, and 993:0.7after 4 hours. After 4 hours 40 minutes, the reaction mixture wastransferred to a 1-L hydrogenation vessel and 5% Pd/C (3.2 g) (DegussaE101 o/w, H₂O 56.2%) was added. Hydrogenation proceeds at 46-52 psig atroom temperature overnight (about 18 h). The mixture was filtered, andrinsed with about 50 ml water. 250 ml of filtrate was obtained, to whichwas added 25 ml butanol, yielding a mixture having pH of 2.86. Whilekept at less than 30° C., or at about 19.6° C., the filtrate wasbasified with 57.5 g of 50% NaOH, resulting in a pH of 9.05. The mixturewas stirred for about one hour at room temperature, filtered, washedwith water (4×50 ml), yielding a brown solid. The wet cake was dried at93° C. at 25″ Hg overnight, yielding 44.2 g, 87.2% yield, of oxymorphoneas a light brown solid.

Example 3 Crude Oxymorphone from CPS-O

A mixture of CPS-O (6.92 g contains 76% (5.26 g, 17.7 mmol) oforipavine), meta-chloroperoxybenzoic acid (MCPBA, 4.30 g) and glacialacetic acid (52 ml) is stirred at room temperature for 5 hours. Theamount of oripavine is then expected to be not more than 1% by HPLCanalysis. To the resulting 14-hydroxymorphinone mixture is added 5% Pd/C(0.55 g) and hydrogenation proceeds at room temperature at 48 psig ofhydrogen for about 18 hours. The amount of unreacted14-hydroxymorphinone is expected to be not more than 0.5% by HPLCanalysis. The mixture is filtered to remove the catalyst and thefiltrate is evaporated to almost dryness. The residue is dissolved inwater and basified to pH 9 by ammonium hydroxide. The solids arecollected by filtration and dried at 90° C. and under 25-inch Hg ofvacuum for 3 hours to give crude oxymorphone (approximately 95% yieldexpected).

Example 4 Purified Oxymorphone

A suspension of the crude oxymorphone (20.0 g, 66 mmol) and water (120ml) was stirred at 45-55° C. Tartaric acid (5.5 g) was added to adjustthe pH to 4.35 to complete dissolution. DARCO (1.0 g) and SOLKA-FLOC(1.0 g) were added and stirred at 45-55° C. for 1 hour. The mixture wasfiltered and rinsed with water (10 ml). The filtrate and washings werecombined and to this were added DARCO (1.0 g), SOLKA-FLOC (1.0 g) andsodium bisulfite (0.4 g). The mixture was stirred for 1 hour at 45-55°C., filtered and rinsed with water (10 ml). 1-BuOH (12 ml) was added tothe filtrate and stirred at 45-55° C. 50% NaOH (6.1 g) was added toadjust the pH to 8.56 at 45-55 ° C., in particular, 50.5° C. The slurrywas cooled to room temperature and filtered. Light brown solids werecollected and dried at 65° C. and 25″ Hg vacuum overnight to givepurified oxymorphone (18.2 g, 60 m mol, 91.0% yield).

Example 5 Oxymorphone HCl from Purified Oxymorphone

Purified oxymorphone (17.8 g, 59 mmol) was suspended in 94% aq. ethanol(107 ml) and stirred at 50-60° C. Concentrated hydrochloric acid (32%)was added slowly to adjust the pH to 2.58. The mixture was allowed tocool to room temperature, and then cooled further to 0-10° C., stirredfor 2 hours and filtered then washed with ethanol (3×20 ml). Theisolated solids were dried at 75° C. under 25 inches-Hg overnight togive oxymorphone HCl as white solids (173 g, 51 mmol, 86.7% yield).

This Oxymorphone HCl meets the specifications in the USP 2006 monographfor Oxymorphone Hydrochloride.

Synthesis of Naltrexone Example 6 Preparation of 3-Benzyloripavine (1-1)from CPS-O

A mixture of CPS-O (76% Oripavine, 13.16 g, 44 m mol), benzyl bromide(9.2 g) and potassium bicarbonate (17.6 g) in toluene (200 ml) is heatedto reflux for 4 hours, then cooled and filtered. The filtrate isextracted with dilute acetic acid. Immediately, the extract is basifiedwith ammonium hydroxide to collect 3-benzyloripavine (expected yield:16.19 g; 95% yield).

Example 7 Preparation of 3-Benzyl-17-cyclopropylmethylnororipavine (1-3)through 3-Benzylnororipavine (1-2) from 3-Benzyloripavine (1-1)

A solution of 3-benzyloripavine (11.62 g, 30 mmol), 1-chloroethylchloroformate (5.52 g, 37.8 mmol) and proton sponge (1.1 g) in methylenechloride (80 ml) is heated at reflux for 2 hours. The reaction mixtureis evaporated in vacuo to dryness. The residue is dissolved in methanol(50 ml), heated to reflux for 30 minutes, basified with ammoniumhydroxide, and then evaporated to dryness. To the residue is added(chloromethyl)-cyclopropane (5.14 g, 55.6 m mol), sodium carbonate (14.7g, 139 mmol), and potassium iodide (4.6 g, 28 mmol) in ethanol (250 ml)and heating proceeds at reflux for 20 hours. The mixture is cooled andevaporated in vacuo to dryness. The residue is basified with ammoniumhydroxide and extracted with methylene chloride. The extract is washedwith water, dried with anhydrous sodium sulfate, and evaporated in vacuoto dryness. The residue is chromatographed on silica gel with a elutingsolvent system of methanol/ethyl acetate (10/90 v/v) to give3-benzyl-17-cyclopropylmethylnororipavine (expected yield: 10.93 g; 85%yield).

Example 8 Preparation of naltrexone through3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone (1-4) from3-benzyl-17-cyclopropylmethylnororipavine (1-3)

A mixture of 3-benzyl-17-cyclopropylmethylnororipavine (10 g, 23 mmol),formic acid (90%, 60 ml), D.I. water (3 ml), methanol (10 ml) andhydrogen peroxide (31%, 3.3 ml) is stirred and heated at 40-50° C. for 5hours. The mixture is allowed to cool, then 5% Pd/C (0.5 g) is added,and the mixture is hydrogenated under 25-inch-Hg for 8 hours. Thecatalyst is filtered off. The residue is evaporated in vacuo to drynessto give a crude product, which is re-crystallized from acetone/water togive a white crystalline solid. It is dried at 90° C. under 25 inch-Hgof vacuum for 4 hours to give naltrexone (expected yield: 6.8 g; 86%yield). This product is identical to a USP standard of Naltrexone.

Synthesis of Buprenorphine from CPS-O or Oripavine

Example 9 Preparation of7α-Acetyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine (2-1) fromOripavine

A mixture of oripavine (28.7 g, 96.5 mmol) and methyl vinyl ketone (18ml) in 2-propanol (90 ml) is stirred and heated at reflux for 6 hours.The mixture is cooled to 10° C. and the solids filtered off, washed withcold 2-propanol and dried at 50° C. to produce an anticipated yield of32.9 g (93% yield) of7α-acetyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine.

Example 10 Preparation of7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine (2-2)from 7α-acetyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine (2-1)

A mixture of 7α-acetyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine(20.5 g, 55.8 m mol), benzyl bromide (11.5 g), and sodium carbonate(23.6 g) in toluene (350 ml) is heated at reflux for 4 hours. Thereaction mixture is cooled and washed with water. The organic layer isevaporated in vacuo to dryness to give 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine (24.5 g, 96% yield).

Example 11 Preparation of7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endo-ethenonororipavine(2-4) through7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endo-ethenonororipavine(2-3) from7α-acetyl-3-benzyl-6,7,8.,14-tetrahydro-6,14-endo-ethenooripavine (2-2)

A solution of7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine (6.9 g,15 m mol), 1-chloroethyl chloroformate (2.76 g, 19 m mol) and protonsponge (0.5 g) in methylene chloride (50 ml) is heated at reflux for 2hours. The reaction mixture is evaporated in vacuo to dryness. Theresidue is dissolved in methanol (30 ml). To this is added a few dropsof concentrated hydrochloric acid and heated to reflux for 30 minutesand basified with ammonium hydroxide. This is evaporated to dryness. Tothe residue is added (chloromethyl)-cyclopropane (2.07 g, 28 mmol),sodium carbonate (7.4 g, 64 mmol), and potassium iodide (2.3 g, 14 mmol)in ethanol (150 ml) and heated at reflux for 20 hours. The resultingmixture is cooled and evaporated in vacuo to dryness. The residue isbasified with ammonium hydroxide and extracted with methylene chloride.The extract is washed with water, dried with anhydrous sodium sulfateand evaporated in vacuo to dryness. The residue is chromatographed onsilica gel with a eluting solvent system of methanol/ethyl acetate(10/90 v/v) to give7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endo-ethenonororipavine(expected yield: 6.9 g, 92% yield).

Example 12 Preparation of3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine(2-5) from7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endo-ethenonororipavine(2-4)

To7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endo-ethenonororipavine(6.6 g, 13 mmol) in dry THF (100 ml) is added tert-butyl magnesiumchloride (2.0 M in THF, 8 ml, 16 mmol). The mixture was heated to refluxfor 18 hours, cooled, THF (100 ml) is added and the mixture is quenchedwith saturated magnesium sulfate solution. The solution is separatedfrom the semisolids and evaporated in vacuo to dryness to give3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine(expected yield: 7.5 g, 90% yield).

Example 13 Preparation of buprenorphine from3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine(2-5)

A mixture of3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine(7.2 g, 13 m mol), glacial acetic acid (42 ml), and 5% Pd/C (0.36 g) ishydrogenated at 25 psig hydrogen pressure at 40° C. for 16 hours. Thecatalyst is filtered off and the filtrate evaporated in vacuo todryness. The residue is re-crystallized from ethanol to givebuprenorphine (expected yield: 5.2 g; 86% yield).

Example 14 Preparation of Buprenorphine Hydrochloride

To a solution of buprenorphine (5.1 g, 11 m mol) in ethanol (60 ml) at50-60° C. is added concentrated hydrochloric acid to pH 2.5, the heatingis maintained at 50-60° C. for 2 hours, and cooled to 10-15° C. Themixture is filtered to collect the solid. The solid is washed with coldethanol and dried at 80° C. under 25 inch Hg of vacuum for 4 hours togive the final product (expected yield: 5.3 g, 96% Yield). This productis identical to a USP standard of Buprenorphine Hydrochloride.

Although the present invention has been described in considerable detailwith regard to certain versions thereof, other versions are possible,and alterations, permutations, and equivalents of the version shown willbecome apparent to those skilled in the art upon a reading of thespecification and study of the drawings. Also, the various features ofthe versions herein can be combined in various ways to provideadditional versions of the present invention. Furthermore, certainterminology has been used for the purposes of descriptive clarity, andnot to limit the present invention. Therefore, any appended claimsshould not be limited to the description of the preferred versionscontained herein and should include all such alterations, permutations,and equivalents as fall within the true spirit and scope of the presentinvention.

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the methods of the presentinvention can be carried out with a wide and equivalent range ofconditions, formulations, and other parameters without departing fromthe scope of the invention or any embodiments thereof.

1. A pharmaceutical dosage form comprising buprenorphine or atherapeutically acceptable salt thereof, and at least one excipient,wherein the buprenorphine or a therapeutically acceptable salt thereofis prepared by a method comprising: obtaining a starting material whichis an opiate precursor, a concentrated poppy straw, or a derivativethereof; processing the starting material to form an intermediate withor without a protecting group, wherein the protecting group comprisesany of a benzyl group, a substituted benzyl group, or an aceto group,said intermediate further comprising a secondary amine; forming areaction mixture by combining the intermediate with (i) an inorganichalide salt, (ii) an alkylating agent, (iii) a metal carbonate, and (iv)an organic solvent; heating the reaction mixture under conditions whichallow the intermediate to be alkylated on the secondary amine; formingan alkylated intermediate by allowing the reaction mixture to react, thealkylated intermediate being alkylated on the secondary amine; andfurther processing the alkylated intermediate to obtain buprenorphine ora therapeutically acceptable salt thereof; wherein the excipientcomprises one or more of a carrier vehicle, a stabilizing agent, asolubilizing agent, a lubricating agent, a flow agent, a bulking agent,a control release agent, a disintegrating agent, a binding agent, apigment, a flavoring agent, or a coating agent; and wherein thepharmaceutical dosage form comprises at least one of a tablet, a pill, acapsule, a parenteral formulation, a suppository, a patch, or a powder.2. The pharmaceutical dosage form of claim 1 wherein the startingmaterial comprises a concentrated poppy straw having oripavine as themain alkaloid.
 3. The pharmaceutical dosage form of claim 1 wherein thestarting material comprises greater than about 50% by weight oripavine.4. The pharmaceutical dosage form of claim 1 wherein the inorganichalide salt comprises an inorganic iodide salt.
 5. The pharmaceuticaldosage form of claim 4 wherein the alkylating agent comprises ahalomethylcyclopropane or tosylmethylcyclopropane.
 6. The pharmaceuticaldosage form of claim 5 wherein the metal carbonate comprises sodiumcarbonate or potassium bicarbonate.
 7. The pharmaceutical dosage form ofclaim 6, wherein the heating comprises heating the reaction mixture at atemperature not exceeding the boiling point of the reaction mixture. 8.The pharmaceutical dosage form of claim 7 wherein the organic solventcomprises an alcohol.
 9. The pharmaceutical dosage form of claim 8further comprising purifying the buprenorphine or therapeuticallyacceptable salt thereof.
 10. The pharmaceutical dosage form of claim 9wherein the further processing comprises obtaining buprenorphinehydrochloride.
 11. The pharmaceutical dosage form of claim 4 wherein theinorganic iodide salt comprises potassium iodide.
 12. The pharmaceuticaldosage form of claim 1 wherein the alkylating agent comprises ahaloalkane or a tosylalkane.
 13. The pharmaceutical dosage form of claim12 wherein the alkylating agent comprises a halomethylcyclopropane ortosylmethylcyclopropane.
 14. The pharmaceutical dosage form of claim 13wherein the inorganic halide salt comprises an inorganic iodide salt.15. The pharmaceutical dosage form of claim 14, wherein the heatingcomprises heating the reaction mixture at a temperature not exceedingthe boiling point of the reaction mixture.
 16. The pharmaceutical dosageform of claim 15 wherein the metal carbonate comprises sodium carbonateor potassium bicarbonate.
 17. The pharmaceutical dosage form of claim 12wherein the alkylating agent comprises a halomethylcyclopropane.
 18. Thepharmaceutical dosage form of claim 17 wherein thehalomethylcyclopropane comprises (chloromethyl)cyclopropane.
 19. Thepharmaceutical dosage form of claim 12 wherein the alkylating agentcomprises tosylmethylcyclopropane.
 20. The pharmaceutical dosage form ofclaim 1 wherein the metal carbonate comprises sodium carbonate orpotassium bicarbonate.
 21. The pharmaceutical dosage form of claim 20wherein the metal carbonate comprises sodium carbonate.
 22. Thepharmaceutical dosage form of claim 1 wherein the organic solventcomprises an alcohol.
 23. The pharmaceutical dosage form of claim 22wherein the alcohol comprises ethanol.
 24. The pharmaceutical dosageform of claim 1, wherein the heating comprises heating the reactionmixture at a temperature not exceeding the boiling point of the reactionmixture.
 25. The pharmaceutical dosage form of claim 24 wherein theheating comprises heating under reflux.
 26. The pharmaceutical dosageform of claim 1 further comprising purifying the buprenorphine ortherapeutically acceptable salt thereof.
 27. The pharmaceutical dosageform of claim 1 comprising buprenorphine hydrochloride.